Diaphanous-related formin mDia2 regulates beta2 integrins to control hematopoietic stem and progenitor cell engraftment

Yang Mei; Xu Han; Yijie Liu; Jing Yang; Ronen Sumagin; Peng Ji

doi:10.1038/s41467-020-16911-4

Diaphanous-related formin mDia2 regulates beta2 integrins to control hematopoietic stem and progenitor cell engraftment

Yang Mei^*, Xu Han, Yijie Liu, Jing Yang, Ronen Sumagin, Peng Ji^*

^*Corresponding author for this work

Pathology

Research output: Contribution to journal › Article › peer-review

9 Scopus citations

Abstract

Bone marrow engraftment of the hematopoietic stem and progenitor cells (HSPCs) involves homing to the vasculatures and lodgment to their niches. How HSPCs transmigrate from the vasculature to the niches is unclear. Here, we show that loss of diaphanous-related formin mDia2 leads to impaired engraftment of long-term hematopoietic stem cells and loss of competitive HSPC repopulation. These defects are likely due to the compromised trans-endothelial migration of HSPCs since their homing to the bone marrow vasculatures remained intact. Mechanistically, loss of mDia2 disrupts HSPC polarization and induced cytoplasmic accumulation of MAL, which deregulates the activity of serum response factor (SRF). We further reveal that beta2 integrins are transcriptional targets of SRF. Knockout of beta2 integrins in HSPCs phenocopies mDia2 deficient mice. Overexpression of SRF or beta2 integrins rescues HSPC engraftment defects associated with mDia2 deficiency. Our findings show that mDia2-SRF-beta2 integrin signaling is critical for HSPC lodgment to the niches.

Original language	English (US)
Article number	3172
Journal	Nature communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-16911-4
State	Published - Dec 1 2020

ASJC Scopus subject areas

Physics and Astronomy(all)
Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)

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10.1038/s41467-020-16911-4

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@article{0e9dc699bcda49718bf43015647c2446,

title = "Diaphanous-related formin mDia2 regulates beta2 integrins to control hematopoietic stem and progenitor cell engraftment",

abstract = "Bone marrow engraftment of the hematopoietic stem and progenitor cells (HSPCs) involves homing to the vasculatures and lodgment to their niches. How HSPCs transmigrate from the vasculature to the niches is unclear. Here, we show that loss of diaphanous-related formin mDia2 leads to impaired engraftment of long-term hematopoietic stem cells and loss of competitive HSPC repopulation. These defects are likely due to the compromised trans-endothelial migration of HSPCs since their homing to the bone marrow vasculatures remained intact. Mechanistically, loss of mDia2 disrupts HSPC polarization and induced cytoplasmic accumulation of MAL, which deregulates the activity of serum response factor (SRF). We further reveal that beta2 integrins are transcriptional targets of SRF. Knockout of beta2 integrins in HSPCs phenocopies mDia2 deficient mice. Overexpression of SRF or beta2 integrins rescues HSPC engraftment defects associated with mDia2 deficiency. Our findings show that mDia2-SRF-beta2 integrin signaling is critical for HSPC lodgment to the niches.",

author = "Yang Mei and Xu Han and Yijie Liu and Jing Yang and Ronen Sumagin and Peng Ji",

note = "Funding Information: We thank Baobing Zhao (Shangdong University, China) for technical assistance, Matthew DeBerge, Edward Thorp, and William A. Muller for sharing the fluorescence microscope and other resources, and Naren Ramanan for providing the SRF-VP16 construct. We are grateful to the Northwestern University Center for Advanced Microscopy core for the help with the imaging experiments and Zheng Jenny Zhang for the help with intrafemoral injection. This work was supported by National Institute of Diabetes and Digestive and Kidney Disease (NIDDK) grant R01-DK102718 (P.J.), R01-DK124220 (P.J.), National Heart, Lung, and Blood Institute grant R01-HL148012 (P.J.) and Department of Defense grant CA140119 and CA180214 (P.J.). X.H. is a recipient of an American Heart Association postdoctoral research award. P.J. is a recipient of a Leukemia and Lymphoma Society Scholar Award and a Harrington Discovery Institute Scholar Award. Publisher Copyright: {\textcopyright} 2020, The Author(s).",

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doi = "10.1038/s41467-020-16911-4",

language = "English (US)",

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journal = "Nature Communications",

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T1 - Diaphanous-related formin mDia2 regulates beta2 integrins to control hematopoietic stem and progenitor cell engraftment

AU - Mei, Yang

AU - Han, Xu

AU - Liu, Yijie

AU - Yang, Jing

AU - Sumagin, Ronen

AU - Ji, Peng

N1 - Funding Information: We thank Baobing Zhao (Shangdong University, China) for technical assistance, Matthew DeBerge, Edward Thorp, and William A. Muller for sharing the fluorescence microscope and other resources, and Naren Ramanan for providing the SRF-VP16 construct. We are grateful to the Northwestern University Center for Advanced Microscopy core for the help with the imaging experiments and Zheng Jenny Zhang for the help with intrafemoral injection. This work was supported by National Institute of Diabetes and Digestive and Kidney Disease (NIDDK) grant R01-DK102718 (P.J.), R01-DK124220 (P.J.), National Heart, Lung, and Blood Institute grant R01-HL148012 (P.J.) and Department of Defense grant CA140119 and CA180214 (P.J.). X.H. is a recipient of an American Heart Association postdoctoral research award. P.J. is a recipient of a Leukemia and Lymphoma Society Scholar Award and a Harrington Discovery Institute Scholar Award. Publisher Copyright: © 2020, The Author(s).

PY - 2020/12/1

Y1 - 2020/12/1

N2 - Bone marrow engraftment of the hematopoietic stem and progenitor cells (HSPCs) involves homing to the vasculatures and lodgment to their niches. How HSPCs transmigrate from the vasculature to the niches is unclear. Here, we show that loss of diaphanous-related formin mDia2 leads to impaired engraftment of long-term hematopoietic stem cells and loss of competitive HSPC repopulation. These defects are likely due to the compromised trans-endothelial migration of HSPCs since their homing to the bone marrow vasculatures remained intact. Mechanistically, loss of mDia2 disrupts HSPC polarization and induced cytoplasmic accumulation of MAL, which deregulates the activity of serum response factor (SRF). We further reveal that beta2 integrins are transcriptional targets of SRF. Knockout of beta2 integrins in HSPCs phenocopies mDia2 deficient mice. Overexpression of SRF or beta2 integrins rescues HSPC engraftment defects associated with mDia2 deficiency. Our findings show that mDia2-SRF-beta2 integrin signaling is critical for HSPC lodgment to the niches.

AB - Bone marrow engraftment of the hematopoietic stem and progenitor cells (HSPCs) involves homing to the vasculatures and lodgment to their niches. How HSPCs transmigrate from the vasculature to the niches is unclear. Here, we show that loss of diaphanous-related formin mDia2 leads to impaired engraftment of long-term hematopoietic stem cells and loss of competitive HSPC repopulation. These defects are likely due to the compromised trans-endothelial migration of HSPCs since their homing to the bone marrow vasculatures remained intact. Mechanistically, loss of mDia2 disrupts HSPC polarization and induced cytoplasmic accumulation of MAL, which deregulates the activity of serum response factor (SRF). We further reveal that beta2 integrins are transcriptional targets of SRF. Knockout of beta2 integrins in HSPCs phenocopies mDia2 deficient mice. Overexpression of SRF or beta2 integrins rescues HSPC engraftment defects associated with mDia2 deficiency. Our findings show that mDia2-SRF-beta2 integrin signaling is critical for HSPC lodgment to the niches.

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SN - 2041-1723

VL - 11

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 3172

ER -

Diaphanous-related formin mDia2 regulates beta2 integrins to control hematopoietic stem and progenitor cell engraftment

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